The mechanisms by which cytokine signaling is regulated in cells are not well understood. Recently, a new family of proteins, termed Suppressors of Cytokines Signaling (SOCS), has been identified. SOCS-1 was identified as a potent inhibitor of JAK-STAT signaling. Analysis of DNA databases led to the identification of six additional SOCS family members (SOCS-2 through SOCS-7). The SOCS family of proteins is defined by the presence of a central SH2 domain and a C-terminal SOCS box. The biologic functions of SOCS-2 through SOCS-7 have just begun to be defined. We have sought to define the function of SOCS-7. Towards this goal, we have generated mice that lack SOCS-7 by gene targeting. Our analyses of SOCS-7-deficient mice demonstrate that the mice have several abnormalities. The mice develop an excoriative skin disease, which is associated with elevated levels of IgE. T cells from the mice produce higher levels of IL-4. When backcrossed unto the C571BL/6 strain, the mice die at six weeks of age. These mice have severe hypoglycemia, and enlarged islets in the pancreas. Biochemical analysis suggests that that SOCS-7 can interact with IRS proteins. IRS activation appears to be increased in cells that lack SOCS-7. Together these data lead us to hypothesize that SOCS-7 is a regulator of IRS activation downstream of several different cytokines. We propose to extend these results and to determine the role of SOCS-7 in IRS function and cytokine signaling. Specifically, we propose to: Determine insulin responses in SOCS-7 deficient mice/cells, Determine the mechanisms responsible for the immune phenotype/skin disease in SOCS-7 deficient mice, Define the mechanism(s) by which SOCS-7 alters IRS signaling and Determine the signaling abnormalities in SOCS-6 and SOCS-6/7 deficient mice. [unreadable] [unreadable] [unreadable] [unreadable]